Day 71: BCG vs RCV1

Today's numbers are impressive: over 1.75 million cases worldwide, with well over 100,000 deaths. The US (with over 500,000 cases) has finally pulled ahead of Italy and exceeded 20,000 deaths. The UK probably won't hold on to its 7th place below China for long but remains there now, and Boris Johnson is out of the ICU.

New York State (at 180,000 cases) remains ahead of the major European hotspots. New Jersey is a distant second at 58,000 cases, and the remaining hotspots (Michigan, Pennsylvania, California, Massachusetts, Louisiana, Florida, and Illinois) are all hovering around 20,000 cases. Michigan has locked down for real this time, forbidding travel between homes and "public or private gatherings of any size."

Massachusetts' numbers are down again today, with 1886 new cases (up 9%) and 87 deaths. The state is now tracking deaths in long-term care facilities (304 total) along with infections (2645, which includes health care workers) and infected facilities (190). Also of note, the sidewalks of one street in Beverly have been declared one-way.

With Wyoming jumping on the bandwagon, all 50 states (plus 4 territories and the District of Columbia) have declared disasters simultaneously for the first time.

So, why us? You've heard this explanation here before, but since the media has picked up on another paper (apparently the fifth) about the correlation between tuberculosis vaccination and low case fatality rates from coronavirus, you're about to hear it four more times.

The Bacillus Calmette–Guérin (BCG) vaccine uses a live, attenuated strain of Mycobacterium bovis (yes, it's a real vaccine, perhaps even more so than vaccina). It protects against tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae and M. lepromatosis) to some extent, for a couple of decades. It has long been known to protect against other respiratory diseases indefinitely, by a still unknown mechanism; it is also sometimes used in the treatment of bladder cancer. Nevertheless, adoption of BCG vaccine varies by country, perceived risk of TB, and time; see the BCG World Atlas for lots of details.

1. Back in the day, PlagueBlog covered the first preprint on this topic, Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study, by Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, and Gonzalo H. Otazu, at several New York institutions. They said:

We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19. We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. We also found that BCG vaccination also reduced the number of reported COVID-19 cases in a country.

They controlled for income and also charted start years of BCG vs. deaths for countries that do or did vaccinate.

2. Another early paper, BCG vaccination may be protective against Covid-19 by Paul K. Hegarty, Ashish Kamat, Helen Zafirakis, and Andrew DiNardo (two Brits and two Texans) quantified both the infection and death rates over a fifteen day period in March at almost 10 times lower with BCG vaccination. They did note that "[c]ountries that have a booster injection of BCG 7 to 14 years later had no better outcomes than those with a single inoculation only."

3. The story currently in the news is about a preprint by researchers at Johns Hopkins that estimated a death rate only 6 times lower with BCG: Differential COVID-19-attributable mortality and BCG vaccine use in countries, by Anita Shet, Debashree Ray, Neelika Malavige, Mathuram Santosham, and Naor Bar-Zeev. The mortality rate is 5.8 times lower in vaccinated populations than in the unvaccinated. The average death rate per 1 million people in vaccinated countries is 0.6, while in unvaccinated countries it is 8.6. (If you're curious about country by country data, take a look at this supplemental figure.)

4. An even more recent paper, Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19 by Martha K. Berg, Qinggang Yu, Cristina E. Salvador, Irene Melani, and Shinobu Kitayama at the University of Michigan, compared infection and death rates in the first 30 days of a country's outbreak to their BCG status. Countries with vaccination policies that did not last into this century (e.g., Spain, Germany) turned out to be equivalent to those who never vaccinated (e.g., the US, Italy). In the supplemental material, they "predict" the numbers for an alternate US with full BCG vaccination:

This analysis applied to the number of cases yielded a predicted value of 11.28, which translates to 79488.86 cases (compared to the actual 213372 cases reported in the US by April 1). This analysis applied to the number of deaths yielded a predicted value of 4.54, which translates to 93.97 deaths (compared to the actual 2467 deaths reported in the US by March 29).

5. There seem to be more than five such papers, so I'm picking a fifth from among the related preprints at medRxiv that contradicts the others: Association Between BCG Policy is Significantly Confounded by Age and is Unlikely to Alter Infection or Mortality Rates by Stefan Kirov of Bristol Myers Squibb. The title says quite a bit, but the author also notes a confounding correlation between BMI and BCG policy: countries with lower BMI also have BCG vaccination. (Obesity is a known risk factor for coronavirus.) He attempts to make a spurious connection between rubella vaccination and (poor) COVID-19 outcomes as a sort of cautionary example, but rubella vaccination dates back to 1964 at the earliest (while BCG is over a hundred years old) and thus is much more confounded by age than BCG coverage could possibly be. Rubella is also a poor choice of counterexample because rubella vaccine (RCV1) coverage has been fairly consistent across the western world (except, notably, in Italy), where the contrasts in outcome despite few cultural and biological confounders led to such a baroque theory as BCG in the first place.

One preprint from yesterday goes full on in the rubella direction with a study of the MMR vaccine: Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19 by Robin Franklin, Adam Young, Bjoern Neumann, Rocio Fernandez, Alexis Joannides, Amir Reyahi, and Yorgo Modis (mostly in Cambridge, England). Though they accept the BCG theory at face value and postulate that adoption of the MMR vaccine might follow a pattern similar to that of BCG, for this paper the confounding element of age for BCG is the primary explanatory factor. Age is strongly correlated with MMR coverage because MMR only dates back to the early 70's, and its constituent vaccines only date to the late 60's. Because rubella vaccine was also given to women of childbearing age, immunity to COVID-19 would be increased differentially for women over 50 vs. men of the same age. (Unfortunately the figures for this in the paper are mostly unlabelled and inscrutable.)

They also found similarities in the viral genomes of SARS-CoV-2 and the measles, mumps, and rubella viruses; there are quite a few details there, but no wet results yet. However, they have collected rubella immunoglobulin data in severe vs. mild cases of COVID-19:

A further prediction of our hypothesis is that there should be a specific rise in rubella Immunoglobulin G (IgG) titres in COVID-19 patients, and that these should correlate with disease burden as a marker of immunogenicity against SARS-CoV2 [...]

Patients with a high severity illness had on average increased levels of rubella IgG (161.9+147.6 IU/ml) compared to patients with a moderate severity of disease (74.5+57.7 IU/ml) (Fig. 5). In comparison, Immunoglobulin M (IgM) levels were 0.21+0.16 IU/ml in severe disease and 0.26+0.21 IU/ml in moderate disease. Whilst we accept that it is possible that this trend could be representative of preinfection protection to rubella infection, it is not possible to determine this. In a study of 160 women of child bearing age, the IgG levels of non-infected patients measured between 24-143 IU/ml, suggesting that it is unlikely that those who developed severe symptoms of the disease had IgG levels far in excess of this prior to infection.

Day 61: April Fools

The civet saw its shadow, so we're expecting six more weeks of quarantine. Or something like that.

PlagueBlog is saddened to report the death of Star Wars actor Andrew Jack from coronavirus, and hopes he was able to leave a Do-Not-CGI order behind.

The world has exceeded 911,000 cases, and the US has surpassed the 200k mark and is already at 205,000 cases with 4,500 deaths. Italy is at 110,000 with 13,000 deaths, and Spain at 100,000 with 9,000 deaths. New York State is at 83,000 cases with 1,900 deaths, with New Jersey the runner-up at 22,000 cases but only 355 deaths.

There's an interesting preprint at medRxiv correlating the varying rates of COVID-19 morbidity and mortality across countries with their rates of tuberculosis vaccination:

BCG vaccination has been reported to offer broad protection to respiratory infections. We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19. We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. We also found that BCG vaccination also reduced the number of reported COVID-19 cases in a country.

You can check out your country's BCG vaccination policy at the BCG World Atlas. Most notably, Spain had a child vaccination program from 1965 to 1981 only, though it appears that Basque children may still be getting vaccinated.

The Bozeman Daily Chronicle reports an undue touristic interest in Montana. The governor has expressed legal qualms about closing the border, trusting in the usual quarantine period instead. PlagueBlog recommends applying the National Guard to the issue instead.

The AP reports that Wisconsin is calling out the National Guard to staff polling sites for their primary next week, even though even Bernie recommends postponing the primary. PlagueBlog also recommends they save the Guard for a real election.

CNN Philippines reports that Duterte has declared open season on quarantine protestors. PlagueBlog is surprised it took him this long.

Time expresses the usual doubts about China's numbers, though in slightly different language than the usual urn-focussed story. Instead, Time opens with China's moving case counting standards:

After several days of trumpeting just a handful of new COVID-19 cases, on Wednesday China once again switched up exactly what that means, and included asymptomatic infections of the coronavirus in its official statistics for the first time.[...]

It was the eighth different definition of what constitutes a COVID-19 infection in China’s official statistics since the outbreak began in late December, with critics arguing that the lack of clarity has made it harder for other nations to adequately understand and prepare for the disease.

P.S. Our numbers are in: Massachusetts is up 1,118 cases (17%) to 7,738, with 33 additional deaths (122 overall). The state conducted a hundred-odd tests while Quest did 2,300 or so. Over 50,000 people have been tested; about 15% were positive.

The governor has also launched an independent investigation of the situation at Holyoke Soldiers' Home.

P.P.S. WFSB Hartford reports that a six-week-old baby has died of coronavirus there.

P.P.P.S. Something I didn't notice in our numbers at first was the death of 31-year-old Riley Rumrill of Suffolk County, an former Alabaman with pre-existing conditions (apparently asthma and obesity), and our youngest victim to date.

P.P.P.P.S. Also, there seems to be another Holyoke Soldiers' Home-level outbreak of stupid going on at the Life Care Center of Nashoba Valley in Littleton, MA. The town felt the need to publicize the facility's bad behavior in a press release.

TB at the OCME

Via an unnamed source: The Boston Herald reports that state health officials will give a press conference later today about a tuberculosis outbreak at the Office of the Chief Medical Examiner.

The sources differed on whether the testing was routine or the result of a recent positive case within the troubled office.
Regardless, the two sources confirmed that at least three employees of the OCME tested positive. At least one employee has been prescribed a nine-month regimen of medication to treat the symptoms and will also undergo monthly liver testing.
“They are trying to test as many people as possible,” said one source. “People are back working. As far as I know they are not walking around wearing face masks. I dont know where they got it. They probably got it from the building.”
Another source, who is familiar with law enforcement issues, said that one or two medical examiners and at least three clerical workers were affected to some degree by the TB outbreak. The office employs about 60 people.
Dr. Joseph Prahlow, president of the National Association of Medical Examiners, said TB was known to affect medical examiners’ offices. “It’s a recognized potential hazard of the work that we do,” he said.

Apocalyptic XDR-TB

Via ProMED-mail: Reuters reports on the "apocalyptic scenario" of an epidemic of extremely drug-resistant tuberculosis and a return "to the pre-antibiotic era":

XDR-TB cases are particularly difficult to treat, and a patient could infect other people for years, according to Mario Raviglione, director of the WHO's Stop TB Department.
"That is the big threat here. If you have more and more of these cases, you will automatically magnify the problem by having transmission going on to other individuals ... Once they become infected they are sort of a time bomb," Raviglione said.
"If this is kept unchecked and goes on, then you may also see an apocalyptic scenario where the present epidemic of TB is replaced by an epidemic of TB which is now fully resistant to everything," he added.

it's hard to maintain one's alarmist reputation when the WHO is more alarmed than you are...

The Typhoid Traveller

Pretty much everyone, including The New York Times, reports on the travelling tuberculosis patient who may have infected two intercontinental flights full of people before being picked up sneaking home from Montreal and quarantined by the CDC--reportedly the first person to be subject to a federal isolation order since a smallpox patient was quarantined in 1963.

The Atlanta Journal-Constitution has an interview with the Typhoid Traveller in which he tells his side of the story of his ill-fated honeymoon:

Katkowsky and CDC officials say they only knew that the man's TB was resistant to many drugs before he left, but that the tests showing he had the most serious form of TB — XDR TB — only came back after he was in Europe. The test results came back on May 21, Fulton County officials said.
The man says he and his bride were in Rome on their honeymoon when they got a message to call the CDC. The CDC official said that they needed to cancel their trip and return home and that the CDC would call the next day with travel information.
The patient says he and his wife canceled plans to move on to Florence the next day as they awaited the CDC's instructions.
The next day, instead of giving the couple travel arrangements, the man said a CDC staff member told him he'd need to turn himself into Italian health authorities the next morning and agree to go into isolation and treatment in that country for an indefinite period of time.
"I thought to myself: 'You're nuts.' I wasn't going to do that. They told me I had been put on the no-fly list and my passport was flagged," the man said.
The man said the CDC told him he could not fly aboard a commercial airliner with his disease. "We asked about the CDC jet and they said no, there wasn't funding in the budget to use the jet," he said.

Johne's Disease in Western Australia

The Australian reports an outbreak of Johne's Disease in Western Australian cattle after a twelve year lull:

Bovine Johne's Disease was confirmed yesterday [July 10th] in a beef herd near Albany, about 400km south of Perth.
It is the first case of its kind in Western Australia since 1994, but Animal Health Australia said the disease was known to have infected about 1350 cattle herds in NSW, Victoria, South Australia and Tasmania.
The highly infectious disease, which is most common in dairy cows, wastes the animal's intestines, preventing the absorption of minerals and proteins.

Johne's Disease is caused by Mycobacterium avium paratuberculosis and is suspected of causing Crohn's Disease in humans. The University of Wisconsin School of Veterinary Medicine has a webpage devoted to the controversy:

The triggering event for Crohn's disease is thought to occur early in life and then be followed by a 15-30 year incubation or latency period. Johne's disease also has a long interval between infection with M. paratuberculosis and onset of clinical signs (2-10 years). Clinical signs in both diseases are seldom seen before sexual maturity. Interestingly, a strong inverse relationship was found between Crohn's disease and gastric cancer using data from 26 countries.

PARA, the Paratuberculosis Awareness & Research Association, has more information on the bacterial theory:

In the early 1900's, the disease we call today "Crohn's disease" was characterized as an infectious disease, specifically intestinal tuberculosis. However, by the early 1930's, definitive classification (proof) that this disease was infectious was not forthcoming. More specifically, when Dr. Burrill B. Crohn failed to prove an infectious cause in 1932, the disease became formally known as "Crohn's disease" (named after Dr. Crohn) and the search for an infectious cause was largely discontinued.

Typhoid Helga

Via ProMED-mail: Eurosurveillance reports on a tuberculosis outbreak at a Stockholm nursery school:

A female assistant at a nursery in a wealthy suburb of Stockholm was diagnosed with smear positive advanced pulmonary tuberculosis in August 2005. She had lost weight and been coughing for several months before diagnosis. The chest x ray showed bilateral cavitary lesions. Infection with an isoniazid-resistant strain of Mycobacterium tuberculosis was confirmed on culture.
All children and adults with a presumed exposure at the nursery were listed and examined. One three year old boywas found to be ill with fever, was admitted to hospital immediately, and diagnosed with primary tuberculosis with hilar adenopathy.
In total 141, children were exposed and of these, 35 (25%) had a TST ≥ 10mm and/or an abnormal chest x ray. Out of 20 children with an abnormal chest x ray, eight had bronchoalveolar infiltrates with hilar adenopathy and 12 hilar adenopathy only. One seven year old girl had a disseminated tuberculosis.

Boston TB Scare

Via ProMED-mail: Channel 5 reports on a tuberculosis scare involving a surgical intern and possibly 1600 exposed patients at four local hospitals. State health officials are investigating.

Anyone who thinks they may have been exposed should contact their physician, the hospital or the Boston Public Health Commission at 617-534-5611.

Consumption consumption

The New York City Department of Health and Mental Hygiene warns against consumption of some Mexican cheeses--namely, those contaminated with Mycobacterium bovis (bovine tuberculosis), which can cause illness and (rarely) death in humans.

The Health Department has identified 35 cases of tuberculosis caused by M. bovis in city residents between 2001 and 2004. In one of those cases, a 15-month-old child who died in March 2004 was later determined to have died from complications due to M. bovis infection.

If Found, Please Return to Biohazard Facility

From ProMED-mail:

On 6 Oct 2004 at the railway station of Sants de Barcelona, a blue paper bag was stolen from the owner of a clinical laboratory. It contained 5 glass tubes, 15cm long x 2cm wide, with black stoppers, containing cultures of Mycobacterium tuberculosis. They were wrapped in absorbent paper inside an opaque white plastic container with a black double cap. This was wrapped in brown parcel paper, with a letter describing the contents, which are highly contagious.

The finder is asked to contact urgently the Cuerpo Nacional de Policia, tel. 091, the local police, tel. 092, and the Servicio de Emergencias de la Generalitat, tel. 112.